An Essential role for DeltaFosB in the median preoptic nucleus in the sustained hypertensive effects of chronic intermittent hypoxia.
An Essential role for DeltaFosB in the median preoptic nucleus in the sustained hypertensive effects of chronic intermittent hypoxia.
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DOI：
10.1161/hypertensionaha.112.193789
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Nestler EJ
中科院分区：
文献类型：
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作者：
Cunningham JT;Knight WD;Mifflin SW;Nestler EJ
阻塞性睡眠呼吸暂停（OSA）的主要临床特征之一是清醒时持续的高血压和交感神经活动升高。慢性间歇性缺氧（CIH），与OSA相关的低氧血症的动物模型，产生类似的持续血压升高。本研究旨在探讨正中视前核（MnPO）内ΔFosB在CIH相关的平均动脉压（MAP）持续升高中的作用。在MnPO中向大鼠注射病毒载体，所述病毒载体单独表达绿色荧光蛋白（GFP）或GFP加抑制ΔFosB的转录效应的显性阴性构建体。在GFP注射的大鼠和未注射的对照组中，在间歇性低氧暴露和常氧暴露期间，暴露于CIH 7天使MAP增加7-10 mmHg。MnPO ΔFosB的显性负性抑制不影响间歇性低氧暴露期间MAP的变化，但显著降低常氧黑暗期CIH血压反应的持续成分。抑制MnPO ΔFosB可减少室旁核和延髓头端腹外侧区的FosB/ΔFosB染色，但对孤束核无影响。PCR-阵列分析确定了5个AP-1调节基因表达的MnPO增加CIH曝光：ace 1，ace 2，nos 1，nos 3，prdx 2和map 3 k3。在暴露于CIH的大鼠中，MnPO中ΔFosB的显性负抑制阻断了这些基因中除Prdx 2外的每一个的表达增加。ΔFosB可能介导持续CIH高血压所必需的MnPO的转录活性，表明神经适应可能有助于OSA的昼夜高血压。
One of the main clinical features of obstructive sleep apnea (OSA) is sustained hypertension and elevated sympathetic activity during waking hours. Chronic intermittent hypoxia (CIH), animal model of the hypoxemia associated with OSA, produces a similar sustained increase in blood pressure. This study determined the role of ΔFosB in the median preoptic nucleus (MnPO) in the sustained increase in mean arterial pressure (MAP) associated with CIH. Rats were injected in the MnPO with viral vectors that expressed green fluorescent protein (GFP) alone or GFP plus a dominant negative construct that inhibits the transcriptional effects of ΔFosB. In GFP injected rats and uninjected controls, 7 day exposure to CIH increased MAP by 7–10 mmHg during both intermittent hypoxia exposure and normoxia. Dominant negative inhibition of MnPO ΔFosB did not affect changes in MAP during intermittent hypoxia exposure but significantly reduced the sustained component of the blood pressure response to CIH during the normoxic dark phase. Inhibition of MnPO ΔFosB reduced the FosB/ΔFosB staining in the paraventricular nucleus and rostral ventrolateral medulla but not the nucleus of the solitary tract. PCR-array analysis identified five AP-1 regulated genes expressed in the MnPO that were increased by CIH exposure: ace1, ace2, nos1, nos3, prdx2, and map3k3. Dominant negative inhibition of ΔFosB in the MnPO blocked increased expression of each of these genes in rats exposed to CIH except for Prdx2. ΔFosB may mediate transcriptional activity in MnPO necessary for sustained CIH hypertension suggesting that neural adaptations may contribute to diurnal hypertension in OSA.